1. Field of the Invention
This invention relates to transdermal molecular transportation. More specifically, this invention relates to methods and apparatus for the regulation of skin permeabilization and analysis of analytes in extracted body fluid.
2. Description of the Related Art Drugs are routinely administered either orally or by injection. The effectiveness of most drugs relies on achieving a certain concentration in the bloodstream. Although some drugs have inherent side effects which cannot be eliminated in any dosage form, many drugs exhibit undesirable behaviors that are specifically related to a particular route of administration. For example, drugs may be degraded in the GI tract by the low gastric pH, local enzymes or interaction with food or drink within the stomach. The drug or disease itself may forestall or compromise drug absorption because of vomiting or diarrhea. If a drug entity survives its trip through the GI tract, it may face rapid metabolism to pharmacologically inactive forms by the liver, the first-pass effect. Sometimes the drug itself has inherent undesirable attributes such as a short half-life or a narrow therapeutic blood level range.
Recently, efforts aimed at eliminating some of the problems of traditional dosage forms involve transdermal delivery of the drugs (TDD). Topical application has been used for a very long time, mostly in the treatment of localized skin diseases. Local treatments, however, only require that the drug permeate the outer layers of the skin to treat the diseased state, with little or no systemic accumulation. Transdermal delivery systems are designed for, inter alia, obtaining systemic blood levels, and topical drug application. For purposes of this application, the word “transdermal” is used as a generic term to describe the passage of substances into, out of, to, and through the skin.
TDD offers several advantages over traditional delivery methods, including injections and oral delivery. When compared to oral delivery, TDD avoids gastrointestinal drug metabolism, reduces first-pass effects, and provides sustained release of drugs for up to seven days, as reported by Elias in Percutaneous Absorption: Mechanisms-Methodology-Drug Delivery, Bronaugh, R. L. Maibach, H. I. (Ed), pp 1-12, Marcel Dekker, New York, 1989.
The transport of drugs to, into, out of, and through the skin is complex since many factors influence their permeation. These include the skin structure and its properties, the penetrating molecule and its physical-chemical relationship to the skin and the delivery matrix, and the combination of the skin, the penetrant, and the delivery system as a whole. Particularly, the skin is a complex structure. There are at least four distinct layers of tissue: the nonviable epidermis (stratum corneum, SC) the viable epidermis, the viable dermis, the subcutaneous connective tissue. Located within these layers are the skin's circulatory system, the arterial plexus, and appendages, including hair follicles, sebaceous glands, and sweat glands. The circulatory system lies in the dermis and tissues below the dermis. The capillaries do not actually enter the epidermal tissue but come within 150 to 200 microns of the outer surface of the skin.
In comparison to injections, TDD can reduce or eliminate the associated pain and the possibility of infection. Theoretically, the transdermal route of drug administration could be advantageous in the delivery of many therapeutic drugs, including proteins, because many drugs, including proteins, are susceptible to gastrointestinal degradation and exhibit poor gastrointestinal uptake. Proteins, such as interferon, are cleared rapidly from the blood and need to be delivered at a sustained rate in order to maintain their blood concentration at a high value. Transdermal devices are also easier to use than injections.
In spite of these advantages, very few drugs and no proteins or peptides are currently administered transdermally for clinical applications because of the low skin permeability to drugs. This low permeability is attributed to the SC, the outermost skin layer which consists of flat, dead cells filled with keratin fibers (keratinocytes) surrounded by lipid bilayers. The highly-ordered structure of the lipid bilayers confers an impermeable character to the SC (Flynn, G. L., in Percutaneous Absorption: Mechanisms-Methodology-Drug Delivery; Bronaugh, R. L., Maibach. H. I. (Ed). pages 27-53, Marcel Dekker, New-York 1989). Several methods have been proposed to enhance transdermal drug transport, including the use of chemical enhancers, i.e., the use of chemicals to either modify the skin structure or to increase the drug concentration in a transdermal patch (Burnette, R. R., in Developmental Issues and Research Initiatives; Hadgraf J., Guy, R. H., Eds., Marcel Dekker: 1989; pp. 247-288; Junginger, et al. in Drug Permeation Enhancement; Hsieh, D. S., Eds., pp. 59-90; Marcel Dekker, Inc. New York 1994) and the use of applications of electric fields to create transient transport pathways (electroporation) or to increase the mobility of charged drugs through the skin (iontophoresis) (Prausnitz Proc. Natl. Acad. Sci. USA 90, 10504-10508 (1993); Walters, K. A., in Transdermal Drug Delivery: Developmental Issues and Research Initiatives, Ed. Hadgraf J., Guy, R. H., Marcel. Dekker, 1989). Another approach that has been explored is the application of ultrasound.
Ultrasound has been shown to enhance transdermal transport of drugs across human skin, a phenomenon referred to as sonophoresis (Levy, J. Clin. Invest. 1989, 83, 2974-2078; Kost and Langer in “Topical drug Bioavailability, Bioequivalence, and Penetration”; pp. 9.1-103, Shah V. P., Maibach H. I., Eds. (Plenum: New York, 1993). For example, U.S. Pat. No. 4,309,989 to Fahim and U.S. Pat. No. 4,767,402 issued to Kost et al. both describe the use of ultrasound in conjunction with transdermal drug delivery. U.S. Pat. No. 4,309,989 discloses the topical application of a medication using ultrasound with a coupling agent such as oil. Ultrasound at a frequency of at least 1000 kHz and a power of one to three W/cm2 was used to create selective localized intracellular concentration of a zinc-containing compound for the treatment of herpes simplex virus.
U.S. Pat. No. 4,309,989, the disclosure of which is incorporated by reference in its entirety, discloses the use of ultrasound for enhancing and controlling transdermal permeation of a molecule, including drugs, antigens, vitamins, inorganic and organic compounds, and various combinations of these substances, through the skin and into the circulatory system. Ultrasound having a frequency of about 20 kHz and having an intensity between about 0 and 3 W/cm2 is used essentially to drive molecules through the skin and into the circulatory system.
Although a variety of ultrasound conditions have bee used for sonophoresis, the most commonly used conditions correspond to therapeutic ultrasound (frequency in the range of between one MHz and three MHz, and intensity in the range of between above zero and two W/cm2) (such as that described in the Kost et al. patent). It is a common observation that the typical enhancement induced by therapeutic ultrasound is less than ten-fold. In many cases, no enhancement of transdermal drug transport has been observed upon ultrasound application. Accordingly, a better selection of ultrasound techniques is needed to induce a higher enhancement of transdermal drug transport by sonophoresis.
Application of low-frequency ultrasound (between about 20 and 200 kHz) can dramatically enhance transdermal transport of drugs, as well as the extraction and measurement of analyte, as described in PCT/US96/12244 by Massachusetts Institute of Technology. Transdermal transport enhancement induced by low-frequency ultrasound was found to be as much as 1000-fold higher than that induced by therapeutic ultrasound. Another advantage of low-frequency sonophoresis as compared to therapeutic ultrasound is that the former can induce transdermal transport of drugs which do not passively permeate across the skin.
Ultrasound gels may be used as couplings in most medical applications of ultrasound energy. Use of these gels may be messy and labor-intensive. To overcome problems associated with applying ultrasound with gels and other coupling agents, patches containing the required components have been developed. A patch adheres to a clean area of the skin, and drug molecules are continually absorbed through the skin into the bloodstream for systematic distribution. These patches include a drug-containing layer provided near an ultrasonic oscillator. Drug absorption is ensured by the action of the ultrasonic waves from the oscillator. The amount of drug released may be controlled by varying the ultrasonic wave output from the oscillator, as described in U.S. Pat. No. 5,007,438 to Tachibana, et al., the disclosure of which is incorporated by reference in its entirety. U.S. Pat. No. 4,821,740 to Tachibana et al. discloses a kit for providing external medicines that includes a drug containing layer and an ultrasonic oscillator for releasing the drugs for uptake through the surface of the skin. The transducer may be battery powered. The application of the ultrasound causes the medication to move from the device to the skin and then the ultrasound energy may be varied to control the rate of administration through the skin.
U.S. Pat. No. 5,421,816 to Lipkovker describes ultrasonic energy that releases a stored drug and forcibly moves the drug through the skin of an organism and to the blood stream. A housing includes a cavity defined by an assembly of ultrasonic transducers and separated from the skin by a polymeric membrane that stores the drug to be delivered. The ultrasonic transducer assembly includes a flat, circular ultrasonic transducer that defines the top of a truncated cone and a polarity of transducer segments that define the walls of the cone. The resonant frequency of the planar transducer is lower than the resonant frequency of the transducer segments. The planar, flat, circular transducer generates a fixed frequency in the 5 kHz to 1 MHz range, and ultrasonic stimuli impulses for a predetermined period of time, such as 10-20 seconds.
Between the stimuli pulse periods, the transducer segments receive variable frequency ultrasonic pumping pulses. The variable frequency ultrasonic pumping pulses lie in the 50 MHz to 300 MHz range. The variable frequency ultrasonic pumping pulses are applied to opposing transducer segments. The transducer segments create beams that impinge on the skin at an oblique angle to create a pulsating wave. Further, the variable frequency ultrasonic pumping pulses are applied to opposing transducer segments in a rotating manner to create pulsating waves in the skin in a variety of directions. The stimuli pulses cause the planar transducer to produce an ultrasonic wave that excites the local nerves in a way that trauma, such as heat and force, excites local nerves. The variable frequency ultrasonic pumping pulses cause the transducer segments to produce ultrasonic waves in both the polymeric membrane and the skin. The ultrasonic waves pump the drug to the polymeric membrane and, then, through skin openings into the underlying blood vessels.
Thus ultrasound energy may serve to enhance the flux of active permeate molecules through the skin and other biological membranes by providing an active energy source, in addition to passive diffusion, to push or pump molecules through pores and channels.
In addition to there being a need to deliver drugs through the skin, there is a major medical need to extract analytes through the skin. For example, it is desirable for diabetics to measure blood glucose several times per day in order to optimize insulin treatment and thereby reduce the severe long-term complications of the disease. Currently, diabetics do this by pricking the highly vascularized fingertips with a lancet to perforate the skin, then milking the skin with manual pressure to produce a drop of blood, which is then assayed for glucose using a disposable diagnostic strip and a meter into which this strip fits. This method of glucose measurement has the major disadvantage that it is painful, so diabetics do not like to obtain a glucose measurement as often as is medically indicated.
Therefore, many groups are working on non-invasive, and less invasive means to measure glucose, such as micro lancets that are very small in diameter, very sharp, and penetrate only to the interstitium (not to the blood vessels of the dermis). A small sample, from about 0.1 to two μl, of interstitial fluid is obtained through capillary forces for glucose measurements. Other groups have used a laser to breach the integrity of the stratum corneum and thereby make it possible for blood or interstitial fluid to diffuse out of such a hole or to be obtained through such a hole using pneumatic force (suction) or other techniques. An example of such a laser based sampling device is disclosed in U.S. Pat. No. 5,165,418 to Tankovich and WPI ACC No: 94-167045/20 by Budnik (assigned to Venisect, Inc.).
A problem with methods that penetrate the skin to obtain interstitial fluid is that interstitial fluid occurs in the body in a gel like form with little free fluid and, in fact, is even under negative pressure that limits the amount of free interstitial fluid that can be obtained. When a very small hole is made in the skin, penetrating to a depth such that interstitial fluid is available, it takes a great deal of mechanical force (milking, vacuum, or other force) to obtain the requisite quantity of blood, or interstitial fluid, used in a glucose meter.
Channeling of ultrasound geometrically is one way to apply ultrasound to a small area. Channeling of ultrasound is disclosed in PCT Patent Application No. PCT/US97/11559 entitled “Ultrasound Enhancement of Transdermal Transport” by Sontra L. P. et al., filed Jun. 30, 1997, and incorporated by reference in its entirety. The oscillation of a small element near or in contact with the surface of the skin is another way to apply ultrasound to a small area. Large forces can be produced locally, resulting in cavitation, mechanical oscillations in the skin itself, and large localized shearing forces near the surface of the skin. The element can also produce acoustic streaming, which refers to the large convective flows produced by ultrasound. This appears to aid in obtaining a sample of blood or interstitial fluid without having to “milk” the puncture site. Ultrasound transducers are known to rapidly heat under continuous operation, reaching temperatures that can cause skin damage. Heat damage to the skin can be minimized by using a transducer that is located away from the skin to oscillate a small element near the skin. In the case of analyte extraction, compounds present on the surface of and/or in the skin can contaminate the extracted sample. The level of contamination increases as skin surface area increases. Surface contamination can be minimized by minimizing the surface area of ultrasound application. Thus, skin permeability can be increased locally, and transiently through the use of the methods and devices described herein, for either drug delivery or measurement of analyte.
Moreover, it has been disclosed that the application of ultrasound is only required once for multiple deliveries or extractions over an extended period of time rather than prior to each extraction or delivery. That is, it has been shown that if ultrasound having a particular frequency and a particular intensity is applied, multiple analyte extractions or drug deliveries may be performed over an extended period of time. For example, if ultrasound having a frequency of 20 kHz and an intensity of about 10 W/cm2 is applied, the skin retains an increased permeability for a period of up to four hours. This is described more particularly in U.S. patent application Ser. No. 09/227,623 entitled “Sonophoretic Enhanced Transdermal Transport” by Mitragotri et al., filed on Jan. 8, 1999, and in PCT Application No. PCT/US99/00437 entitled “Sonophoretic Enhanced. Transdermal Transport” by Sontra Medical et al., filed Jan. 8, 1999 the disclosures of which are hereby incorporated by reference in their entireties.
Nevertheless, the amount (e.g., duration, intensity, duty cycle etc.) of ultrasound necessary to achieve this permeability enhancement varies widely. Several factors of the nature of skin must be considered. For example, the type of skin which the substance is to pass through varies from species to species, varies according to age (e.g., the skin of an infant has a greater permeability than that of an older adult), varies according to local composition, thickness and density, varies as a function of injury or exposure to agents such as organic solvents or surfactants, and varies as a function of some diseases, such as psoriasis, or abrasion. Moreover, as discussed above, overexposure to ultrasound and cavitation can cause damage to the skin through heating and increased pressure. Therefore, it is necessary to control the ultrasound application in order to enable clinically useful transdermal transport.